Six versus eight doses of rituximab in patients with aggressive B cell lymphoma receiving six cycles of CHOP: results from the "Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas" (PETAL) trial.

Standard first-line treatment of aggressive B cell lymphoma comprises six or eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus eight doses of rituximab (R). Whether adding two doses of rituximab to six cycles of R-CHOP is of therapeutic benefit has not been systematically investigated. The Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial investigated the ability of [18F]-fluorodesoxyglucose PET scanning to guide treatment in aggressive non-Hodgkin lymphomas. Patients with B cell lymphomas and a negative interim scan received six cycles of R-CHOP with or without two extra doses of rituximab. For reasons related to trial design, only about a third underwent randomization between the two options. Combining randomized and non-randomized patients enabled subgroup analyses for diffuse large B cell lymphoma (DLBCL; n = 544), primary mediastinal B cell lymphoma (PMBCL; n = 37), and follicular lymphoma (FL) grade 3 (n = 35). With a median follow-up of 52 months, increasing the number of rituximab administrations failed to improve outcome. A non-significant trend for improved event-free survival was seen in DLBCL high-risk patients, as defined by the International Prognostic Index, while inferior survival was observed in female patients below the age of 60 years. Long-term outcome in PMBCL was excellent. Differences between FL grade 3a and FL grade 3b were not apparent. The results were confirmed in a Cox proportional hazard regression model and a propensity score matching analysis. In conclusion, adding two doses of rituximab to six cycles of R-CHOP did not improve outcome in patients with aggressive B cell lymphomas and a fast metabolic treatment response.

The hypomorphic TERT A1062T variant is associated with increased treatment-related toxicity in acute myeloid leukemia.

Hypomorphic germline variants in TERT, the gene encoding the reverse transcriptase component of the human telomerase complex, occur with a frequency of 3-5% in acute myeloid leukemia. We analyzed the clinical and prognostic impact of the most common TERT A1062T variant in younger patients with acute myeloid leukemia intensively treated within two prospective multicenter trials. Four hundred and twenty patients (age 17-60 years) were analyzed for the TERT A1062T variant by direct sequencing. Fifteen patients (3.6%) carried the TERT A1062T variant. Patients with the TERT A1062T variant had a trend towards less favorable and more intermediate 2/adverse karyotypes/genotypes according to the European Leukemia Net classification. In univariate and multivariate analysis, patients with the TERT A1062T variant had a significantly inferior overall survival compared to wild-type patients (6-year overall survival 20 vs. 41%, p = 0.005). Patients with the TERT A1062T variant showed a high rate of treatment-related mortality: 5/15 (33%) died during induction therapy or in complete remission as compared to 62/405 (15%) of the wild-type patients. In patients with the TERT variant, 14/15 (93%) suffered from non-hematological/non-infectious grade 3/4 adverse events (mostly hepatic and/or mucosal) as compared to 216/405 (53%) wild-type patients (p = 0.006). In multivariate analysis, the TERT A1062T variant was an independent risk factor predicting for adverse events during induction chemotherapy. In conclusion, the TERT A1062T variant is an independent negative prognostic factor in younger patients with acute myeloid leukemia and seems to predispose those patients to treatment-related toxicity.

Valproic acid in combination with all-trans retinoic acid and intensive therapy for acute myeloid leukemia in older patients.

The outcome of patients with acute myeloid leukemia who are older than 60 years has remained poor because of unfavorable disease characteristics and patient-related factors. The randomized German-Austrian AML Study Group 06-04 protocol was designed on the basis of in vitro synergistic effects of valproic acid (VPA) and all-trans retinoic acid with chemotherapy. Between 2004 and 2006, 186 patients were randomly assigned to receive 2 induction cycles with idarubicin, cytarabine, and all-trans retinoic acid either with VPA or without (STANDARD). In all patients, consolidation therapy was intended. Complete remission rates after induction tended to be lower in VPA compared with STANDARD (40% vs 52%; P = .14) as a result of a higher early death rate (26% vs 14%; P = .06). The main toxicities attributed to VPA were delayed hematologic recovery and grade 3/4 infections, observed predominantly during the second induction cycle. After restricting VPA to the first induction cycle and reducing the dose of idarubicin, these toxicities dropped to rates observed in STANDARD. After a median follow-up time of 84 months, event-free and overall survival were not different between the 2 groups (P = .95 and P = .57, respectively). However, relapse-free-survival was significantly superior in VPA compared with STANDARD (24.4% vs 6.4% at 5 years; P = .02). Explorative subset analyses revealed that AML with mutated Nucleophosmin 1 (NPM1) may particularly benefit from VPA. This trial was registered at www.clinicaltrials.gov as #NCT00151255.

Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: results of the AML Study Group (AMLSG).

In this study, we evaluated the frequency and prognostic impact of DNMT3A mutations (DNMT3A(mut)) in 1770 younger adult patients with acute myeloid leukemia (AML) in the context of other genetic alterations and the European LeukemiaNet (ELN) classification. DNMT3A(mut) were found in 20.9% of AMLs and were associated with older age (P < .0001), higher white blood cell counts (P < .0001), cytogenetically normal AML (CN-AML; P < .0001), NPM1 mutations (P < .0001), FLT3 internal tandem duplications (P < .0001), and IDH1/2 mutations (P < .0001). In univariable and multivariable analyses, DNMT3A(mut) did not impact event-free, relapse-free (RFS), or overall survival (OS) in either the entire cohort or in CN-AML; a negative prognostic effect was found only in the ELN unfavorable CN-AML subset (OS, P = .011). In addition, R882 mutations vs non-R882 mutations showed opposite clinical effects-unfavorable for R882 on RFS (all: hazard ratio [HR], 1.29 [P = .026]; CN-AML: HR, 1.38 [P = .018]) and favorable for non-R882 on OS (all: HR, 0.77 [P = .057]; CN-AML: HR, 0.73 [P = .083]). In our statistically high-powered study with minimized selection bias, DNMT3A(mut) represent a frequent genetic lesion in younger adults with AML but have no significant impact on survival end points; only moderate effects on outcome were found, depending on molecular subgroup and DNMT3A(mut) type.

Prognostic impact of IDH2 mutations in cytogenetically normal acute myeloid leukemia.

Mutations in the nicotinamide adenine dinucleotide phosphate(+)-dependent isocitrate dehydrogenase gene 2 (IDH2) have recently been found in patients with acute myeloid leukemia (AML) as well as in patients with leukemic transformation of myeloproliferative neoplasms. We analyzed 272 adult patients with cytogenetically normal AML (CN-AML) for the presence of IDH2 mutations in codons R140 and R172. IDH2 mutations of amino acid 140 or 172 could be identified in 12.1% of CN-AML patients, with the majority of mutations (90%) occurring at position R140. The incidence of IDH2 mutations in AML patients with aberrant karyotypes (n = 130) was significantly lower (3.8%, P = .006). IDH2 mutations were mutually exclusive with mutations in IDH1. IDH2 mutation status alone or in combination with IDH1 mutations had no impact on response to therapy, overall survival, and relapse-free survival in patients with CN-AML. In conclusion, IDH2 mutations are frequently found in CN-AML, but in our analysis these mutations did not influence treatment outcome. This study was registered at www.clinicaltrials.gov as #NCT00209833.

Impact of complete surgical resection on outcome in aggressive non-Hodgkin lymphoma treated with immunochemotherapy.

BACKGROUND: Surgical resection is considered to be of purely diagnostic value in aggressive lymphoma. Evidence for an impact on outcome is scant and restricted to retrospective observations. METHODS: In the "Positron Emission Tomography-guided Therapy of Aggressive non-Hodgkin Lymphomas" (PETAL) trial, patients with a negative baseline positron emission tomography (PET) scan were documented in a prospective observational substudy. Baseline PET-negative patients with the absence of lymph node enlargement on computed tomography and a negative bone marrow biopsy were considered to have undergone complete lymphoma resection. RESULTS: Eighty-two of 1,041 patients (7.9%) had a negative baseline PET scan, and 67 were included in this analysis. All were treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), plus rituximab for CD20-positive lymphomas. Among 52 patients with diffuse large B-cell lymphoma (DLBCL), 48 had completely resected disease. Their outcome tended to be better than that of 115 baseline PET-positive stage I DLBCL patients treated in the main part of the PETAL trial (2-year progression-free survival 92.7% [95% confidence interval 84.7-100] versus 88.4% [82.5-94.3], P = .056; 2-year overall survival 92.7% [84.7-100] versus 93.7% [89.2-98.2], P = .176), but this was restricted to patients below the age of 60 years (2-year progression-free survival 100% versus 92.2% [84.8-99.6], P = .031; 2-year overall survival 100% versus 95.9% [90.2-100], P = .075). In peripheral T-cell lymphoma, eight of 11 patients had completely resected disease. In contrast to DLBCL, complete resection was not associated with improved outcome compared to the control. CONCLUSION: Young patients with early stage DLBCL may benefit from complete lymphoma resection prior to immunochemotherapy.

Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL): A Multicenter, Randomized Phase III Trial.

Purpose Interim positron emission tomography (PET) using the tracer, [18F]fluorodeoxyglucose, may predict outcomes in patients with aggressive non-Hodgkin lymphomas. We assessed whether PET can guide therapy in patients who are treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Patients and Methods Newly diagnosed patients received two cycles of CHOP-plus rituximab (R-CHOP) in CD20-positive lymphomas-followed by a PET scan that was evaluated using the ΔSUVmax method. PET-positive patients were randomly assigned to receive six additional cycles of R-CHOP or six blocks of an intensive Burkitt's lymphoma protocol. PET-negative patients with CD20-positive lymphomas were randomly assigned or allocated to receive four additional cycles of R-CHOP or the same treatment with two additional doses rituximab. The primary end point was event-free survival time as assessed by log-rank test. Results Interim PET was positive in 108 (12.5%) and negative in 754 (87.5%) of 862 patients treated, with statistically significant differences in event-free survival and overall survival. Among PET-positive patients, 52 were randomly assigned to R-CHOP and 56 to the Burkitt protocol, with 2-year event-free survival rates of 42.0% (95% CI, 28.2% to 55.2%) and 31.6% (95% CI, 19.3% to 44.6%), respectively (hazard ratio, 1.501 [95% CI, 0.896 to 2.514]; P = .1229). The Burkitt protocol produced significantly more toxicity. Of 754 PET-negative patients, 255 underwent random assignment (129 to R-CHOP and 126 to R-CHOP with additional rituximab). Event-free survival rates were 76.4% (95% CI, 68.0% to 82.8%) and 73.5% (95% CI, 64.8% to 80.4%), respectively (hazard ratio, 1.048 [95% CI, 0.684 to 1.606]; P = .8305). Outcome prediction by PET was independent of the International Prognostic Index. Results in diffuse large B-cell lymphoma were similar to those in the total group. Conclusion Interim PET predicted survival in patients with aggressive lymphomas treated with R-CHOP. PET-based treatment intensification did not improve outcome.

Phase III study of second-line chemotherapy for advanced non-small-cell lung cancer with weekly compared with 3-weekly docetaxel.

PURPOSE: A phase III study to determine whether a weekly docetaxel schedule improves the therapeutic index compared with the classic 3-weekly schedule. PATIENTS AND METHODS: Patients with stage IIIB-IV non-small-cell lung cancer (NSCLC) were randomly assigned to docetaxel 75 mg/m2 on day 1 every 3 weeks (3-weekly) and 35 mg/m2 on days 1, 8, and 15 (weekly) for < or = eight cycles. End points included survival (primary), toxicity, and response. RESULTS: Of 215 patients enrolled, 208 (103 in the 3-weekly arm and 105 in the weekly arm) were assessable for response. At baseline, 24.5% of patients (51 out of 208) had received prior paclitaxel therapy and 43.3% of patients (90 out of 208) had been progression-free for more than 3 months after first-line therapy. After 12 months' follow-up, median survival was 6.3 months (95% CI, 4.68 to 7.84 months) with 3-weekly docetaxel and 9.2 months (95% CI, 5.83 to 12.59 months) with weekly docetaxel (P = .07) after a median of four (range, one to eight) and two (range, one to eight) treatment cycles, respectively. Overall, response rates were 12.6% v 10.5% with 3-weekly versus weekly docetaxel. Significantly fewer patients reported grade 3 to 4 toxicities with weekly docetaxel versus 3-weekly docetaxel (P < or = .05). There were significantly lower rates of grade 3 to 4 anemia (P < or = .05), leucopenia (P < .0001), and neutropenia (P < or = .001) with weekly versus 3-weekly treatment. No grade 3 to 4 thrombocytopenia or mucositis was reported. CONCLUSION: Weekly docetaxel 35 mg/m2 demonstrated similar efficacy and better tolerability than standard 3-weekly docetaxel 75 mg/m2 and can be recommended as a feasible alternative second-line treatment option for patients with advanced NSCLC.

Single nucleotide polymorphism in the mutational hotspot of WT1 predicts a favorable outcome in patients with cytogenetically normal acute myeloid leukemia.

PURPOSE: We assessed the prognostic impact of a known single nucleotide polymorphism (SNP) located in the mutational hotspot of WT1 in patients with cytogenetically normal acute myeloid leukemia (CN-AML) in the context of other prognostic markers. PATIENTS AND METHODS: WT1 exons 7 and 9 from 249 CN-AML patients from multicenter treatment trials AML-SHG Hannover 0199 (Clinical Trials Identifier NCT00209833) and 0295, and 50 healthy volunteers were analyzed by direct sequencing. NPM1, FLT3, CEBPA, and MLL were assessed for mutations and WT1 expression was quantified. RESULTS: The minor allele of SNP rs16754 (WT1(AG/GG)) was found in 25.7% of CN-AML patients' blasts and germline DNA and in 36% of healthy volunteers. Patient characteristics, frequencies of mutations, or WT1 expression levels were similarly distributed between patients homozygous for the major allele compared with patients heterozygous or homozygous for the minor allele. SNP rs16754 status was an independent predictor of relapse-free survival (RFS; hazard ratio [HR], 0.49; 95% CI, 0.3 to 0.81; P = .005) and overall survival (OS; HR, 0.44; 95% CI, 0.27 to 0.74; P = .002) in multivariate analysis. The favorable effect of SNP rs16754 was stronger in NPM1/FLT3-ITD (internal tandem duplication of the FLT3 gene) high-risk patients compared with NPM1/FLT3-ITD low-risk patients. Favorable prognosis could not be identified by any other known low-risk marker in half the patients with at least one minor allele (13% of all patients). No difference for complete remission rate, RFS, or OS was found between patients with or without acquired WT1 mutations. CONCLUSION: WT1 SNP rs16754 may be a novel independent favorable-risk marker in CN-AML patients that might improve risk and treatment stratification.

Impact of IDH1 R132 mutations and an IDH1 single nucleotide polymorphism in cytogenetically normal acute myeloid leukemia: SNP rs11554137 is an adverse prognostic factor.

PURPOSE: We assessed the prognostic impact of IDH1 R132 mutations and a known single nucleotide polymorphism (SNP) located in the same exon of the IDH1 gene in patients with cytogenetically normal acute myeloid leukemia (CN-AML) in the context of other prognostic markers. PATIENTS AND METHODS: IDH1 exon four was directly sequenced in 275 CN-AML patients from two subsequent AML multicenter treatment trials and 120 healthy volunteers. Moreover, mutations in NPM1, FLT3, CEBPA, and WT1 were analyzed, and mRNA expression of IDH1 was quantified. RESULTS: IDH1 R132 mutations were found in 10.9% of CN-AML patients. IDH1 SNP rs11554137 was found in 12% of CN-AML patients and 11.7% of healthy volunteers. IDH1 R132 mutations had no impact on prognosis. In contrast, IDH1 SNP rs11554137 was an adverse prognostic factor for overall survival in univariate and multivariate analysis. Other significant factors were age, NPM1/FLT3 mutational status, WT1 SNP rs16754, and platelet count. The impact of IDH1 SNP rs11554137 was most pronounced in the NPM1/FLT3 high-risk patients (either NPM1 wild-type or FLT3-internal tandem duplication positive). Patients with IDH1 SNP rs11554137 had a higher expression of IDH1 mRNA than patients with two wild-type alleles. CONCLUSION: IDH1 SNP rs11554137 but not IDH1 R132 mutations are associated with an inferior outcome in CN-AML.